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Unexpectedly, given the well-established role played by regulatory T cells (Tregs) in establishing an immunosuppressive tumor microenvironment, Yaqing Zhang and collegues observed accelerated tumor progression after depletion of Tregs in mouse models of spontaneous Kras-driven pancreatic cancer. Notably, Treg depletion failed to elicit a productive anti-tumor response at early or late-stage disease in spontaneous models, whereas depletion was associated with attenuated tumor growth and an increase in cytotoxic CD8+ T cell markers in mice transplanted with syngenic pancreatic cancer cell lines. Regardless of the tumor model, precancerous lesions in Treg-depleted mice displayed identical total numbers of fibroblasts as those in control animals, yet reduced smooth muscle actin staining in the fibrotic microenvironment was observed in animals lacking Tregs. Depletion of T regs in mice with spontaneous pancreatic cancer was associated with a consistent increase in myeloid cells with an immunosuppressive phenotype, including upregulated expression of arginase and programmed death-ligand 1. Flow-sorted epithelial cells and fibroblasts isolated from tumor-bearing pancreata after Treg depletion displayed increased expression of several C-C motif chemokine ligands by RNAseq, and treatment with a commercial CCR1 inhibitor delayed carcinogenesis in the models. The results reveal a complex cross-talk in the pancreas giving rise to compensatory immunosuppression mechanisms that involve multiple cell lineages.